This invention concerns prosthetic materials. More particularly, it concerns a biocompatible material that exhibits reverse phase behavior.
Osteogenic bone repair materials are known in the art. These materials contain an osteogenic material, such as demineralized bone powder in a carrier, such as glycerol. See, e.g., U.S. Pat. No. 5,290,558, issued Mar. 1, 1994 to O""Leary et al., and U.S. Pat. No. 5,284,655, issued Feb. 8, 1994 to Bogdansky et al.
The carrier of the bone material in the art is a liquid, having a viscosity generally somewhere between runny and paste-like. xe2x80x9cRunnyxe2x80x9d bone repair compositions have the advantage of being relatively easy to apply to and fill a bone defect, however they are disadvantageous in that the material also tends to readily flow from the defect site. Conversely, bone repair compositions with a xe2x80x9cpaste-likexe2x80x9d consistency are harder to apply to a defect, yet tend to remain positioned at the defect once applied. Additionally, when any of the bone repair compositions in the art are placed in vivo and become warmed, they become even less viscous; the decrease in viscosity is due to the addition of thermal energy to the composition.
Accordingly, there is a need for a bone repair composition that is easy to apply to a defect site, and which remains positioned at the site once placed at the site.
Disclosed is a biocompatible composition to facilitate repair of connective tissues. The composition can comprise demineralized bone powder, and, a carrier comprising a means for achieving reverse phase thermodynamic characteristics when mixed with the bone powder. The composition can be substantially liquid at 0xc2x0 C., and substantially more viscous at 35xc2x0 C., such that the composition has a consistency like that of paste floor wax or like solid shoe wax. The means for achieving reverse phase characteristics can comprise a block copolymer, such as a poly(oxyalkylene) block copolymer, which can be a poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblock copolymer. The triblock copolymer can be a compound of the formula: 
The means for achieving reverse phase characteristics comprises a poloxamer, such as poloxamer 407. The block copolymer can be a solid dispersed in a biocompatible solvent such as sterile water.
Preferably, the carrier comprises a carrier of 25 weight percent of a block copolymer dispersed in 75 weight percent of a biocompatible solvent. To vary the consistency of the composition, the weight percentage of demineralized bone powder or other solid can be varied relative to the weight percentage of the carrier in the composition. For example, a paste-like form of the composition comprises 50 weight percent of bone powder and 50 weight percent of a carrier. A gel-like embodiment of the composition comprises 30 weight percent of bone powder and 70 weight percent of a carrier.
The bone powder of the composition can comprise particles with a median length to a median thickness ratio of about 1.742:1, a mean length of 0.25-1 mm (250-1,000 microns), and a mean thickness of about 0.5 mm (500 microns).
Also disclosed is a method to facilitate the development of bone tissue, said method comprising: providing a biocompatible connective tissue repair composition comprising demineralized bone powder, and, a carrier comprising a means for achieving reverse phase thermodynamic characteristics when mixed with the bone powder; and, placing the composition in a bony defect of a mammal. A prosthetic object can also be placed in the bony defect. The method can also comprise coating a portion of the prosthetic object with the biocompatible composition, and in this embodiment the step of placing the composition and the step of placing a prosthetic object can be contemporaneous.
By xe2x80x9creverse phasexe2x80x9d or xe2x80x9creverse thermal behaviorxe2x80x9d is intended a material that exhibits a physical property of becoming more viscous or solidified upon addition of thermal energy. It is believed that the solidification occurs by a mechanism other than that due to evaporation and corresponding loss of liquid.
As used herein, xe2x80x9cambient temperaturexe2x80x9d is 25xc2x0 C., plus or minus 5xc2x0 C.
As used herein, xe2x80x9cbody temperaturexe2x80x9d is 37xc2x0 C., plus or minus 5xc2x0 C.
As used herein, a xe2x80x9cbony defectxe2x80x9d or xe2x80x9cbone defect sitexe2x80x9d is bony environment of a mammal which comprises some viable bone tissue. The defect can be congenital, caused by trauma, or caused by disease.
xe2x80x9cOsteoinductivexe2x80x9d materials cause undifferentiated cells to differentiate into a committed bone cell lines.
xe2x80x9cOsteoinductivexe2x80x9d materials provide support for cells of a bone cell lineage, e.g., permitting cells of a bone cell lineage to grow along or through a matrix or lattice.
In a preferred embodiment, the composition of the present invention is a flowable liquid when applied to a bony defect, whereupon the composition becomes increasingly solidified or viscous as it warms to ambient and is further solidified as it warms to body temperature. Upon being warmed to body temperature, a preferred composition of the invention is a solid or highly viscous fluid. The reverse phase compositions in accordance with the invention are significantly different in principle from bone repair materials in the art, and do not function in the same way.
The composition comprises a therapeutic material for treating one or more connective tissues; and, a carrier. The therapeutic material can be a material to facilitate repair of connective tissues, i.e., a xe2x80x9cconnective tissue repair material.xe2x80x9d The carrier achieves reverse phase characteristics when mixed with the therapeutic material.
The therapeutic material can be a material that is osteoinductive, osteoconductive, or a material that is osteoinductive and osteoconductive. The therapeutic material can be xenogeneic, allogeneic, or autogenic. The therapeutic material can be alloplastic. As appreciated by one of ordinary skill in the art, the therapeutic material can comprise combinations of various therapeutic materials.
Examples of osteoinductive material include but are not limited to bone powder (mineralized or demineralized), tissue growth factor beta (TGF-xcex2) types 1 through 13, bone morphogenetic protein (BMP) types 1 through 15, or combinations thereof.
Examples of therapeutic materials that are osteoconductive include but are not limited to xenogeneic bone (mineralized or demineralized); the xenogeneic bone can also be subjected to deproteination. Presently preferred xenogeneic source are porcine and bovine.
Therapeutic materials that are osteoinductive and osteoconductive include particulate human allograft, e.g., of demineralized bone.
Examples of alloplastic materials comprise gypsum, coralline hydroxyapatite, synthetic hydroxyapatite, calcium carbonate, calcium phosphate, calcium sulfate, biodegradable polymeric materials, or combinations thereof.
A presently preferred composition comprises demineralized osteogenic bone powder in a carrier; the composition can be applied to a bone defect site to induce new bone growth. This composition of the present invention comprises demineralized bone particles or granules (referred to herein as xe2x80x9cdemineralized bone powderxe2x80x9d) in an inert biocompatible carrier.
In a preferred embodiment, the particles/granules have a median length to median thickness ratio about 1.742:1, a mean length of 0.25-1 mm (250-1,000 microns) and a mean thickness of about 0.5 mm (500 microns).
The presently preferred biocompatible carrier of the composition of the invention is a material that confers reverse phase thermodynamic properties on the composition. The use of PLURONIC(copyright) F127 as a component of an osteointegration promoting composition is set forth in U.S. Pat. No. 5,503,558, issued Apr. 2, 1996 to the inventor herein, Cameron C. L. Clokie; and in PCT International Publication No. WO 95/13099. In a presently preferred embodiment, the carrier comprises a polymer marketed by BASF (Parsipanny, N.J.) as PLURONIC(copyright) F127. PLURONIC(copyright) F127 is a poly(oxyalkylene) block copolymer; more specifically, a poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) poly(oxyethylene) triblock copolymer; it is a member of a class of compounds called poloxamers. (Schmolka, xe2x80x9cA Review of Block Polymer Surfactantsxe2x80x9d J. Am. Oil Chemists Soc. 54:110-116 (1977)). Several members of the poloxamer family exhibit reverse phase thermodynamic characteristics. PLURONIC(copyright) F127 is also known by the name xe2x80x9cpoloxamer 407.xe2x80x9d (Schmolka, xe2x80x9cA Comparison of Block Polymer Surfactant Gelsxe2x80x9d J. Am. Oil Chemist Soc. 68:206-209 (1991)). PLURONIC(copyright) F127 has an average molecular weight of approximately 12,500. (Schmolka, xe2x80x9cA Comparison of Block Polymer Surfactant Gelsxe2x80x9d J. Am. Oil Chemist Soc. 68:206 -209 (1991)) The structure of the PLURONIC(copyright) F127 polymer is depicted as follows: 
In preferred embodiments of a composition of the present invention, the carrier is a liquid diluted in a solvent or is a solid dispersed in a solvent. In one embodiment, PLURONIC(copyright) F127 is dispersed in a solvent such as sterile water. The PLURONIC(copyright) F127 carrier is vastly different in size, molecular weight, and chemical structure than carriers in the art. The carrier is also substantially different in terms of its functional properties than any carrier of a bone repair material in the art.
The proposed composition has a unique physical property, being flowable at refrigerated temperatures and increasingly solidified at elevated temperatures, such as ambient and body temperatures. This property is referred to in the art as xe2x80x9creverse phasexe2x80x9d or xe2x80x9creverse thermal behaviorxe2x80x9d. Due to the reverse phase property of the proposed composition, the composition is generally manufactured at refrigerated temperatures, such as 5xc2x0 C. Manufacturing is done at refrigerated temperatures to enhance mixing of the components of the composition, since the proposed composition comprising an aqueous suspension of PLURONIC(copyright) F127 begins to become more viscous at ambient temperature, and is increasingly viscous and solidified at body temperature. Generally, a composition of the invention will be twice as viscous at 35xc2x0 C. as it is at 0xc2x0 C.
For example, the preferred PLURONIC(copyright) F127 carrier in the composition of the present invention (when dispersed in an appropriate amount of sterile water), has the unique property of being a liquid at refrigerated temperature and increasingly solidified, then solid at elevated temperature, absent the effects of evaporation and concomitant loss of water. This property is called xe2x80x9creverse phasexe2x80x9d or xe2x80x9creverse thermal behaviorxe2x80x9d because it is the exact opposite of the thermodynamic properties exhibited by standard carriers.
It is believed that the reverse phase property is due, at least in part, to the fact that PLURONIC(copyright) F127 is composed of discrete blocks of both hydrophilic (i.e., oxyethylene) and hydrophobic (i.e., oxypropylene) subunits. (See e.g., Schmolka, xe2x80x9cA Comparison of Block Polymer Surfactant Gelsxe2x80x9d J. Am. Oil Chemist Soc. 68:206-209 (1991)).
In contrast, standard carriers, as well as all liquids, manifest the typical physical property of becoming increasingly flowable upon addition of thermal energy, such as occurs when the liquid is heated to body temperature. However, the preferred carrier in a composition of the present invention becomes less flowable as energy is added to it either by heating or by shaking.
The unique reverse phase thermodynamic properties of the composition of the present invention allow the product to function in a substantially different, and preferred manner relative to other flowable bone repair products. When applied to a bone defect site, the reverse phase property of the preferred carrier provides support characteristics for the composition which are substantially different than the characteristics of standard carriers. Enhanced support is provided by the composition of the invention. The preferred PLURONIC(copyright) F127 carrier of the composition of the present invention helps to provide support characteristics which are unlike those of any standard carrier. This is because the composition is flowable at refrigerated temperature and can thus readily be applied to a bony defect site, but it becomes increasingly viscous and solidified once it is warmed at the site. The solidification of the composition of the present invention achieves several beneficial effects. When solidified, the composition does not flow away from the defect site, and the solidified product immediately augments and facilitates structural support at the defect. Also, since the osteogenic composition of the invention is initially liquid, it readily fills a defect, then becomes solidified and achieves enhanced osteogenesis. Moreover, with preferred compositions of the invention, comprising a sterile aqueous colloidal suspension of PLURONIC(copyright) F127 as a carrier and demineralized bone powder, the carrier will resorb or dissolve after about three days, leaving the osteogenic bone powder at the bone defect site. It is believed to be advantageous that the carrier disperses as this then allows enhanced ingrowth of connective or vascular tissues.
In a composition of the invention, the weight percentages of the therapeutic material and the carrier can each be varied. For example, the weight percent of the therapeutic material can vary between about 20 to 80 weight percent of the composition, and the weight percent of the carrier can vary between about 20 to 80 weight percent of the composition. Furthermore one or more additional components can be present in a composition of the invention, such as antibiotics, analgesic, anti-inflammatory agents, or agents to promote development of connective or circulatory system tissues.